Fibroblast growth factors (FGFs) 19 and 21 are related hormones that have emerged as promising drug candidates for the treatment of metabolic syndrome. Pharmacologically, both FGF19 and FGF21 increase energy expenditure, cause weight loss and improve glucose tolerance, insulin sensitivity and lipid parameters in rodent models of metabolic disease. FGF21 has similar beneficial effects in obese monkeys and in patients with type 2 diabetes. However, the tissues and molecular mechanisms through which FGF19 and FGF21 exert their beneficial effects remain to be determined. In this proposal, we explore the basis for their effects on energy expenditure, weight loss, insulin sensitivity and glycemia. Based on work from our laboratory and others, we hypothesize that FGF19 and FGF21 act directly on the hypothalamus and dorsal-vagal complex in the nervous system to stimulate sympathetic outflow to brown and white adipose tissue depots; and on brown and white adipose tissue to stimulate glucose uptake, fatty acid synthesis and mobilization, and thermogenic gene expression. The net effect of this two-pronged mechanism is increased energy expenditure and weight loss and improved insulin sensitivity. In addition, we hypothesize that FGF19 acts directly on liver to stimulate glycogen synthesis and to suppress gluconeogenesis, which contributes to its beneficial glycemic effects. We propose to test this hypothesis by using diet-induced obese mice in which -Klotho, a cell surface protein that serves as an obligate co-receptor for both FGF19 and FGF21, is selectively eliminated in the nervous system, adipose tissue or liver. Treatment and evaluation of these different tissue-specific -Klotho knockout mouse models in conjunction with complementary in vitro studies with isolated white and brown adipocytes will provide important insights into the tissues and molecular mechanisms whereby FGF19 and FGF21 mediate their pharmacologic effects. We anticipate that these studies will provide important insights into FGF19 and FGF21's mechanism of action and help guide the generation of more efficacious FGF19 and FGF21-based drugs for treating metabolic disease.